scholarly journals Targeted protein degradation: from small molecules to complex organelles—a Keystone Symposia report

Author(s):  
Jennifer Cable ◽  
Eilika Weber‐Ban ◽  
Tim Clausen ◽  
Kylie J. Walters ◽  
Michal Sharon ◽  
...  
2019 ◽  
Vol 7 ◽  
Author(s):  
Mikihiko Naito ◽  
Nobumichi Ohoka ◽  
Norihito Shibata ◽  
Yoshinori Tsukumo

2017 ◽  
Vol 61 (5) ◽  
pp. 517-527 ◽  
Author(s):  
Honorine Lebraud ◽  
Tom D. Heightman

In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified through genetic knockdown. Targeted protein degradation holds the potential to expand the range of proteins that can be effectively modulated. Drugs inducing protein degradation through misfolding or by modulating cereblon (CRBN) substrate recognition are already approved for treatment of cancer patients. The last decade has seen the development of proteolysis targeting chimeras (PROTACs), small molecules that elicit proteasomal degradation by causing protein polyubiquitination. These have been used to degrade a range of disease-relevant proteins in cells, and some show promising efficacy in preclinical animal models, although their clinical efficacy and tolerability is yet to be proven. This review introduces current strategies for protein degradation with an emphasis on PROTACs and the role of click chemistry in PROTAC research through the formation of libraries of preclicked PROTACs or in-cell click-formed PROTACs (CLIPTACs).


Author(s):  
Ming He ◽  
Wenxing Lv ◽  
Yu Rao

Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and reversible chemical knockout tools. At the same time, its challenges and problems also need to be resolved as a fast-developing newchemical biology technology.


2021 ◽  
Vol 28 ◽  
Author(s):  
Yizheng Fang ◽  
Qiaojun He ◽  
Ji Cao

: The evolution in research and clinical settings of targeted therapies has been inspired by the progress of cancer chemotherapy to use small molecules and monoclonal antibodies for targeting specific disease-associated genes and proteins for noninfectious chronic diseases. In addition to conventional protein inhibition and activation strategies as drug discovery modalities, new methods of targeted protein degradation and regulation using molecular glues have become an attractive approach for drug discovery. Mechanistically, molecular glues trigger interactions between the proteins that originally did not interact by forming ternary complexes as protein-protein interaction (PPI) modulators. New molecular glues and their mechanisms of action have been actively investigated in the past decades. An immunomodulatory imide drug, thalidomide, and its derivatives have been used in the clinic and are a class of molecular glue that induces degradation of several neo-substrates. In this review, we summarize the development of molecular glues and share our opinions on the identification of novel molecular glues in an attempt to promote the concept and inspire further investigations.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2471-2471
Author(s):  
James Bradner ◽  
John Paul Shen ◽  
Edward Greenberg ◽  
Teru Hideshima ◽  
Kenneth C. Anderson ◽  
...  

Abstract The response of refractory multiple myeloma to the proteasome inhibitor bortezomib reveals an intriguing sensitivity of this incurable malignancy to perturbations of protein catabolism. However, an overall clinical response rate of approximately 30% as a single agent suggests the importance of chemoresistance mediated by compensatory mechanisms of protein degradation. With proteasome inhibition, juxtanuclear inclusion bodies accumulate. These “aggresomes” are specific cellular structures comprised of chaperones, misfolded proteins, and proteasome components. The cytoplasmic histone deacetylase inhibitor (HDAC6) is essential for aggresome formation. Recently, we have demonstrated robust cytotoxic synergy in multiple myeloma cells between bortezomib and the carboxy-terminal domain-selective inhibitor of HDAC6, tubacin (1). Tubacin is a hydroxamic acid member of a diversity-oriented synthetic chemical library realized and validated previously by members of our laboratory (2). In our study of bortezomib and tubacin in multiple myeloma, we noted the dose-dependent, significant association between cytotoxicity and the marked accumulation of polyubiquitinated proteins in sensitized cells. With an interest in further interruption of the misfolded protein response, we have explored the cytosolic chaperone protein, hsp90, as an additional target using a chemical biologic approach. 17-AAG is an analog of the benzoquinone ansamycin antibiotic geldanamycin, known to bind to the ADP/ATP pocket of hsp90. 17-AAG stabilizes a conformation of the chaperone favoring targeted degradation of its client proteins via recruitment of the hsp70 co-chaperone complex (3). Further supporting this strategy, collaborators have recently identified that HDAC6 binds to and principally mediates the deacetylation of hsp90 (4). Inhibition with non-selective HDAC inhibitors was shown to augment hsp90 acetylation and inhibit ATP binding, resulting in the promotion of protein degradation by polyubiquitination. With the support of these data, we investigated whether the addition of 17-AAG to bortezomib and tubacin results in increased cytotoxicity in multiple myeloma cells. Indeed, we demonstrate potent cytotoxicity in cultured myeloma cells at low concentrations of each small molecule. Focused study of the MM.1S cell line demonstrates that the addition of 17-AAG to tubacin and bortezomib markedly increases the burden of ubiquitinated, cytosolic cellular protein by 24 hours, correlating with enhanced cell killing. These data further credential the protein degradation pathway in multiple myeloma, demonstrate the contribution of targeted, combined approaches with active small molecules, and provide a blueprint for a rational therapeutic strategy.


Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1789
Author(s):  
Dare E. George ◽  
Jetze J. Tepe

The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.


Author(s):  
Xingui Liu ◽  
Xuan Zhang ◽  
Dongwen Lv ◽  
Yaxia Yuan ◽  
Guangrong Zheng ◽  
...  

Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure–activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.


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